Peptidomimetic macrocycles

Abstract

The present invention provides novel peptidomimetic macrocycles and methods of using such macrocycles for the treatment of disease.

1 .- 21 . (canceled) 
     
     
         22 . A method of treating cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically-effective amount of a peptidomimetic macrocycle, wherein the cancer is associated with aberrant beta-catenin activity;
 wherein the peptidomimetic macrocycle comprises:   a) a helical region;   b) a cyclic amino acid;   c) an alpha, alpha disubstituted amino acid, wherein the cyclic amino acid and the alpha, alpha disubstituted amino acid are at positions ranging from i+4 to i+7; and   d) a crosslinker linking the cyclic amino acid and the alpha, alpha disubstituted amino acid within the peptidomimetic macrocycle;   wherein the crosslinker is of the formula:   
       
         
           
           
               
               
           
         
         wherein X is CH 2 , Y is CH 2 , m is 0-10, n is 0-10, o is 0-10, and p is 0-10, and m, n, o, and p are chosen such that: 
         1) the crosslinker has a length equal to 5 carbon-carbon bonds to 22 carbon-carbon bonds; 
         2) the crosslinker has 13 atoms to 33 atoms; and 
         3) the peptidomimetic macrocycle has a ring that has 17 to 82 members. 
       
     
     
         23 . The method of  claim 22 , wherein the helical region comprises an alpha-helical region. 
     
     
         24 . The method of  claim 22 , wherein the crosslinker links the alpha-positions of the cyclic amino acid and the alpha, alpha disubstituted amino acid. 
     
     
         25 . The method of  claim 22 , wherein the peptidomimetic macrocycle modulates an activity of beta-catenin in the subject. 
     
     
         26 . The method of  claim 22 , wherein the peptidomimetic macrocycle antagonizes an interaction between beta-catenin and TCF/LEF proteins in the subject. 
     
     
         27 . The method of  claim 22 , wherein the crosslinker has a length equal to 8 carbon-carbon to 14 carbon-carbon atoms. 
     
     
         28 . The method of  claim 22 , wherein the peptidomimetic macrocycle has a ring that has 17 to 35 members. 
     
     
         29 . The method of  claim 22 , wherein the peptidomimetic macrocycle has a ring that has 17 to 44 members. 
     
     
         30 . The method of  claim 22 , wherein one of the substituents on the alpha, alpha disubstituted amino acid is a methyl group. 
     
     
         31 . A method of treating cancer in a subject in need thereof, the method comprising:
 administering to the subject a therapeutically-effective amount of a peptidomimetic macrocycle, wherein the cancer is associated with aberrant beta-catenin activity;   wherein the peptidomimetic macrocycle comprises a crosslinker linking a first non-natural amino acid and a second non-natural amino acid within the peptidomimetic macrocycle;   wherein the crosslinker has the formula -L 1 -L 2 -;   wherein each L 1  and L 2  is independently alkylene, alkenylene, alkynylene, heteroalkylene, cycloalkylene, heterocycloalkylene, cycloarylene, heterocycloarylene, or [—R 4 —K—R 4 —] n , each being optionally substituted with R 5 ;   wherein each R 4  is independently alkylene, alkenylene, alkynylene, heteroalkylene, cycloalkylene, heterocycloalkylene, arylene, or heteroarylene;   wherein each K is independently O, S, SO, SO 2 , CO, CO 2 , or CONR 3 ;   wherein each R 3  is independently hydrogen, alkyl, alkenyl, alkynyl, arylalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, cycloalkylalkyl, cycloaryl, or heterocycloaryl, optionally substituted with R 5 ;   wherein each R 5  is independently halogen, alkyl, —OR 6 , —N(R 6 ) 2 , —SR 6 , —SOR 6 , —SO 2 R 6 , —CO 2 R 6 , a fluorescent moiety, a radioisotope or a therapeutic agent;   wherein each R 6  is independently —H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkylalkyl, heterocycloalkyl, a fluorescent moiety, a radioisotope or a therapeutic agent;   wherein each n is independently an integer from 1-5.   
     
     
         32 . The method of  claim 31 , wherein the peptidomimetic macrocycle comprises a cyclic amino acid. 
     
     
         33 . The method of  claim 31 , wherein at least one of the two non-natural amino acids is a cyclic amino acid. 
     
     
         34 . The method of  claim 31 , wherein the first non-natural amino acid is a cyclic amino acid. 
     
     
         35 . The method of  claim 34 , wherein the second non-natural amino acid is an alpha, alpha-disubstituted amino acid. 
     
     
         36 . The method of  claim 35 , wherein one of the substituents on the alpha, alpha disubstituted amino acid is a methyl group. 
     
     
         37 . The method of  claim 31 , wherein the crosslinker links the alpha-positions of the first non-natural amino acid and the second non-natural amino acid. 
     
     
         38 . The method of  claim 31 , wherein the peptidomimetic macrocycle comprises a helix. 
     
     
         39 . The method of  claim 31 , wherein the peptidomimetic macrocycle comprises an alpha-helix. 
     
     
         40 . The method of  claim 31 , wherein L 1  and L 2  are independently alkylene, alkenylene, or alkynylene. 
     
     
         41 . The method of  claim 31 , wherein L 1  and L 2  are independently C 3 -C 6  alkylene or C 3 -C 6  alkenylene. 
     
     
         42 . The method of  claim 31 , wherein the peptidomimetic macrocycle modulates an activity of beta-catenin in the subject. 
     
     
         43 . The method of  claim 31 , wherein the peptidomimetic macrocycle antagonizes an interaction between beta-catenin and TCF/LEF proteins in the subject.